The objective of this research project is to identify the inducers and suppressors of the urea cycle enzymes in mammalian liver, and to elucidate the mechanisms by which enzyme induction is accomplished. Eventually, such inducers may make it possible to control the level of these enzymes in human liver. Control mechanisms operative in the arginine biosynthetic pathways of microorganisms will be sought for in mammalian cells and compared with the role of hormones as inducers or suppressors. The experimental systems to be employed are: 1) cell cultures of rat hepatomas which contain the urea cycle enzymes and fetal liver cell explant cultures, and 2) rats, monkeys, and eventually humans. The specific aims of the project are as follows: 1. To determine which amino acids are the most effective inducers in cell and tissue cultures and in intact rats. 2. To test whether inducing amino acids act in part or entirely by releasing glucagon, and whether glucagon induces the enzymes by increasing cellular cyclic AMP. 3. To assess the roles of other hormones as inducers or suppressors. 4. To study whether induction occurs at the level of transcription or translation of genetic information. 5. To detect genetic defects of urea cycle enzymes in children with hyperammonemia, to define the patterns of inheritance, to study the kinetic and protein abnormalities and to attempt therapy with inducing agents.